Background: Autism Spectrum Disorders (ASDs) are common, heritable neurobiologic
conditions of unknown etiology confounded by significant clinical and genetic heterogeneity.
In recent years, array CGH technology has been used to rapidly screen the
genome for pathogenic copy number variants (PCNVs) associated with ASDs and data
from 6 studies suggests that PCNVs contribute to ASD pathogenesis in 6-27% of cases.
However, the role of PCNVs in ASDs remains poorly understood, due to the absence of
comprehensive phenotyping of ASD subjects.
Methods: To address this, we collected detailed clinical, medical, physical and morphologic
information on all subjects and investigated whether these phenotypes would
be good indicators of PCNV risk. We studied somatic phenotypes, as opposed to behavioural
indices that change over time and with treatment, in an attempt to provide
better evidence for the biological/embryological origin of ASDs and help define new
ASD syndromes.
Results: Seven disease-specific and potentially pathogenic CNVs were uncovered
in 6/40 patients (15%). Two changes were de novo and 5 were inherited from normal
parents, but had never been reported in normal populations before. All PCNVs were discovered
in individuals without family history of autism, ranged in sizes from 175kb to
2.5Mb, and revealed 9 good candidate genes. Our results suggest that whilst no single
phenotypic feature investigated associates with PCNV risk, there is an indication that
the presence of phenotypic abnormalities involving multiple body areas may be a better
indicator of PCNVs in ASDs than the presence or number of minor physical anomalies
alone. In addition, our findings lend support to the idea that complex autism, involving
significant dysmorphology, is etiologically distinct from essential autism, with an
increased prevalence of ID, seizures and health problems, and a higher proportion of
individuals without family history of ASDs.
Conclusion: We identified novel areas of chromosomal imbalance associated with
ASDs and provide detailed phenotypic information for every subject for which these
new PCNVs were detected. The extensive phenotyping of affected individuals carrying
clinically relevant CNVs is needed in order to understand their role in the etiology of
autism and ultimately provide earlier and more reliable means for ASD diagnosis and
treatment.